WO1998058674A1 - Compositions pharmaceutiques anti-tumorales reduisant la resistance aux medicaments des cellules tumorales - Google Patents

Compositions pharmaceutiques anti-tumorales reduisant la resistance aux medicaments des cellules tumorales Download PDF

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WO1998058674A1
WO1998058674A1 PCT/IT1998/000169 IT9800169W WO9858674A1 WO 1998058674 A1 WO1998058674 A1 WO 1998058674A1 IT 9800169 W IT9800169 W IT 9800169W WO 9858674 A1 WO9858674 A1 WO 9858674A1
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Prior art keywords
cells
tumour
cell
gpl30
drugs
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PCT/IT1998/000169
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English (en)
Inventor
Gennaro Ciliberto
Rocco Savino
Carlo Toniatti
Natale D'alessandro
Nicolò BORSELLINO
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Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A.
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Priority to AU79315/98A priority Critical patent/AU7931598A/en
Publication of WO1998058674A1 publication Critical patent/WO1998058674A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/204—IL-6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5412—IL-6

Definitions

  • the present invention relates to pharmaceutical compositions with anti-tumour activity that are also capable of decreasing tumour drug resistance. More specifically the invention relates to the use of mutant molecules of human interleukin 6 for preparation of chemotherapy mixes designed to treat human prostate carcinoma .
  • Cancer treatment currently in use includes at least two strategies : surgery and/or chemotherapy- Which of these strategies is used generally depends on the tumour being treated. In some cases, other treatments such as X- ray therapy and cobalt therapy are associated with the treatment indicated above. Generally speaking, all patients undergo chemotherapy associated with various strategic treatments .
  • Chemotherapy usually involves the use of compositions containing a number of molecules with cytotoxic activity. This results in various problems connected to the intrinsic toxicity of the drugs, to the lack of specificity in selecting a tumour cell rather than a "normal" one and furthermore to the response of the tumour cell .
  • a tumour cell has undergone a series of structural and genetic modifications that make it different from a normal cell.
  • a cancer cell for example, has altered its proliferation system, so that it is capable of invading and attacking tissues and organs, and is also capable of "avoiding” the control of the immune system.
  • a tumour mass responds to drug treatment by continuing to select drug resistant cells. For this reason, the ability to kill a tumour cell is connected with the survival systems that are typical of each primary tumour cell and of the cells that are subsequently selected. This is the reason why current cancer treatment provides for treatment using a mixture of chemotherapy drugs, which can result in any case ineffective in the treatment of certain types of tumour form.
  • Drug resistance is in fact almost always the cause and the effect of progression in a tumour that does not respond to treatment.
  • the phenomenon of multiple drug resistance (MDR) is in fact among the basic problems in cancer treatment, which has been dealt with in two ways: on the one hand by studying the resistance mechanisms, on the other hand by using drug preparations consisting of a number of molecules capable of preventing the tumour cell from establishing resistance to a specific drug.
  • cytokines and growth factors are effectively involved in some of the mechanisms of drug resistance of certain tumour forms.
  • Some for example G-CSF or GM-CSF
  • GM-CSF have the effect of increasing the death of tumour cells when adiminstered in association with drugs
  • some others for example interleukin 6
  • interleukin 6 have instead the effects of increasing the survival of the tumour cells in many types of cancer forms, one of the most important of which is prostate cancer.
  • Prostate carcinoma is in fact the most common form of tumour diagnosed in males, which in 1995 was the tumoural form that with the exception of the lung cancer, has reached the highest mortality rate in the United States.
  • radical prostatectomy can be used to treat patients with localised tumours, the majority of patients show an advanced stage of the disease at the time of diagnosis.
  • systematic androgen ablation treatment may be of use when treating patients suffering from prostate cancer, 12-18 months from the start of treatment tumour cells that are independent of the hormones develop. This specific type of tumour form is usually particularly resistant to chemotherapy.
  • IL-6 is in fact a multifunctional molecule with a wide range of action in the stimulation or inhibition of cell growth (depending on the type of target cell) . It is also involved in certain immune mechanisms, and can also have an autocrine or paracrine effect as a growth factor in certain tumours such as multiple myeloma. IL-6 is a factor protecting against cell death in multiple myeloma cells, and inhibits desamethasone- induced apoptosis. It has been observed that IL-6 blocks the cytotoxicity of some anti-cancer agents and biological factors in myeloid leukemic cells.
  • IL-6 represents a resistance factor for cytotoxicity induced by drugs such as etoposide and cisplatinum (hereinafter referred also as VP-16 and CDDP respectively) .
  • VP-16 and CDDP drugs such as etoposide and cisplatinum
  • the IL-6 receptor is a heterodimeric glycoprotein that has been fully identified at molecular level. It is made up of a receptor for the ligand IL6-R ⁇ and a transducer for the signal gpl30. IL-6 promotes sequential formation of a complex between the two molecules: IL6-R ⁇ binds IL-6 with high affinity and then forms a complex with gpl30 that is crucial for signal transduction. This proceeds in cascade to activate tyrosine kinases of the Jak family.
  • IL-6 receptor complex induced by IL-6 is related to those of other cytokines, such as the leukemia inhibitory factor (LIF) , the ciliary neurotrophic factor (CNTF) , interleukin-11 (IL-11) , cardiotrophin 1 (CT-1) and oncostatin M (OM) , which all require gpl30 as signal transducing subunit .
  • LIF leukemia inhibitory factor
  • CNTF ciliary neurotrophic factor
  • IL-11 interleukin-11
  • CT-1 cardiotrophin 1
  • OM oncostatin M
  • Oncostatin M is a 28 kD glycoprotein secreted by activated macrophages and T lymphocytes, originally described for its ability to inhibit the growth of human melanoma A375 cells and also active on other tumour cell lines.
  • this factor can also stimulate cell growth, by an autocrine mechanism, in AIDS related Kaposi sarcoma cells and is capable of eliciting a multitude of other biological effects.
  • the signal is transduced by the protein gpl30.
  • the present invention is based on experimental observation of the PC-3 cells, in which oncostatin M, like IL-6, was shown to play an important part in regulation of the cell proliferation and in drug resistance.
  • oncostatin M like IL-6
  • the inventors have in particular demonstrated that using the gpl30 as a transducer, OM can regulate survival and resistance of prostate cancer cells, and can act as a possible paracrine factor, mimicking and amplifying the effects of IL-6, which is likewise produced in the cell -mediated response of the immune system.
  • IL-6 increases drug resistance in a human prostate carcinoma cell line (Borsellino N. et al . 1995) .
  • the observations made on IL-6 and OM do not exclude the possibility that these factors may have a positive effect also on survival of the tumour cells, preventing necrosis or drug- induced apoptosis. It is also not excluded that IL-6 or OM can have a specific influence on a biochemical drug adaptation mechanism, as was ascertained in kidney tumour cells, that glutathione S- transferase (one of those enzymes that intervene in drug resistance) is over-regulated by IL-6.
  • the inventors have tested the effects of their inhibition on cell proliferation. Therefore the inventors have first tested the capability of inhibitors of both molecules, of blocking cell growth.
  • the inhibitors tested were the IL-6 mutein Tyr31Asp, Gly35Phe, Leu57Asp, Glu59Phe, Asn ⁇ OTrp, Gln75Tyr, Ser76Lys, Serll ⁇ Arg, Vall21Asp, Glnl75Ile, Serl76Arg, Glnl83Ala, hereinafter referred to as Sant 7 (disclosed in the patent application WO 96/34104 and represented in the sequence listing below as SEQ ID NO:l) and antibodies anti-IL-6 as inhibitors of IL-6 mediated effects, and an antisense oligonucleotides in the sequence coding for gpl30 represented as SEQ ID NO: 2 and SEQ ID NO : 3 in the sequence listing
  • Anti-IL-6 antibodies and the IL-6 superantagonist Sant 7 results in fact in inhibition of cell growth and in increasing the sensitivity of PC-3 to the chemotherapy drugs VP-l ⁇ and CDDP by the neutralisation of IL-6 activity.
  • the antisense oligonucleotide was demonstrated to inhibit the effects of IL-6 and of OM on the tumour cells, probably by blocking the signal transduction process .
  • the present invention consisting in pharmaceutical compositions containing at least one of the above mentioned inhibitors in combination with at least one chemotherapic drug, provides a new approach in cancer treatment based on the capability of counteracting the development of refractiveness to the chemotherapy drugs.
  • IL-6 antagonists such as Sant 7 can be of great therapeutic use. It is also true that the effects of IL-6 and OM might be prevented by the use of anti-gpl30 antisense oligonucleotides , or of inhibitors of the tyrosine kinases involved in the biochemical route for signal transduction by gpl3C.
  • Subject of the present invention is a pharmaceutical composition capable of reducing the cell drug resistance to anti-tumour drugs, comprising at least one chemotherapeutic drug and at least one agent capable of inhibiting the transduction of the signal sent by a cytokine having the protein gpl30 as transducer and a pharmaceutically acceptable carrier.
  • compositions in which the chemotherapeutic drugs are etoposide, or analogs thereof, and cisplatin, or analogs thereof .
  • the agents capable of inhibiting the transduction of "the signal sent by a cytokine having the protein gpl30 as transducer is the IL-6 mutein represented by SEQ ID NO:l, or antisense oligonucleotides, fragments or derivatives thereof, in the sequence coding for gpl30.
  • the pharmaceutical compositions above for the preparation of anti-tumour drugs, and for the preparation of drugs having therapeutic effects on human prostate carcinoma .
  • composition of matter characterised by the fact of comprising etoposide, cisplatin and the IL-6 mutein represented by SEQ ID NO : 1.
  • Figure 1 shows the effects of stimulation of cell proliferation by exogenous oncostatin M on the PC-3 cell line after 24 hour incubation, as measured by trypan blue dye exclusion test.
  • the results represent the mean + SD of three different experiments performed in duplicate.
  • a single asterisk indicates P ⁇ 0.05 with respect to the control; a double asterisk indicates P ⁇ 0.01 with respect to the control .
  • Figure 2A shows the effects of IL-6 in combination with monoclonal neutralising antibody anti-human IL-6 on growth of PC-3 cell line after 24 hour incubation, as measured by trypan blue dye exclusion test.
  • the results represent the mean ⁇ SD of three different experiments performed in duplicate.
  • a single asterisk indicates P ⁇ 0.05 with respect to administration of IL-6 alone, the double asterisk indicates P ⁇ 0.01 with respect to administration of IL-6 alone.
  • Figure 2B shows the effects of IL-6 in combination with the IL-6 mutein Sant 7, on growth of PC-3 cell line after 24 hour incubation, as measured by trypan blue dye exclusion test.
  • the results represent the mean ⁇ SD of three different experiments performed in duplicate.
  • a single asterisk indicates P ⁇ 0.05 with respect to administration of IL-6 alone, the double asterisk indicates P ⁇ 0.01 with respect to administration of IL-6 alone.
  • Figure 3 shows the effects of administration of Sant 7 alone, or in combination with oncostatin M on the PC-3 cell line after 24 hours incubation, as measured by trypan blue dye exclusion test. The results represent the mean ⁇ SD of three different experiments performed in duplicate .
  • Figure 4 shows the effects of administration of antisense oligonucleotides against gpl30 (added at a concentration of 10 ⁇ M at 0 h and of 5 ⁇ M at 24 and 48 h) and of its mismatched mutant in combination with oncostatin M (19 ng/ml) on PC-3 cell line after 72 hours incubation, as measured by trypan blue dye exclusion test . The results represent the outcome ⁇ SD of an experiment performed in triplicate. A repeat experiment gave very similar results.
  • the abbreviation ASO indicates antisense oligodeoxynucleotide against gpl30; the abbreviation MUT indicates mismatched mutant of the antisense oligodeoxynucleotide.
  • the human hormone-independent prostate carcinoma PC- 3 cell line was developed by Dr. Arie Belldegrun of the University of California at Los Angeles, Los Angeles, CA.
  • PC-3 cells are available from the American Type Culture Collection, with the entry reference number ATCC CRL 1435.
  • the cells were maintained in complete RPMI 1640 medium (HiClone Laboratories, Logan, UT, USA) supplemented with 10% heat-inactivated fetal calf serum (HyClone) , 1% L-glutamine (HyClone) , 1% pyrovate (HyClone) , and 1% penicillin/streptomycin solution containing 10 u/ml penicillin G and 10 mg/ml streptomycin sulphate.
  • the cells were grown as adherent cells in a humidified atmosphere at 37°C in 5% carbon dioxide .
  • tumour cells When the tumour cells were used experimentally, they were first treated with trypsin-EDTA, washed and resuspended in complete medium. OM ELISA test
  • OM protein The presence of intracellular and extracellular OM protein was determined by ELISA. Briefly, 5 x 10 cells were incubated in complete medium; after 48 hours the cells were treated with trypsin-EDTA and harvested, and the supernatant was separated from the cells by centrifugation. Cells and supernatant were collected to measure the OM content. The cells were resuspended in 1 ml complete medium and the viable cells were counted by the trypan blue dye exclusion test and sonicated. After centrifugation the medium was collected to measure the intracellular content of OM. The determination of both extracellular and intracellular levels of OM was performed by an OM ELISA kit supplied by Amersham (Little Chalfont, England) .
  • the PC-3 cell line was resuspended in complete medium at a concentration of 1 x 10 cells/ml after verifying their viability. Amounts of 1 ml of cell suspension were distributed into each well of a 24-well culture plate (Nunc, Roskilde, Denmark) . After one night the cells were in a state of adhesion. At time 0 h, the culture medium was replaced with 1 ml of fresh complete medium and reagents were added at appropriate concentrations .
  • the oligonucleotides with OM and VP16 were added after 6 h. After 24 hours (and after 72 hours for experiments in combination with other drugs) the cells were harvested by treatment with trypsin. Cell viability was determined by the ability of cells to exclude trypan blue dye. The cells were assessed visually by microscopy, and the number of viable cells was calculated by subtracting the number of cells that stained positive from the total number of cells. The surviving fraction (s.f.) is obtained from the ratio of the number of experimental viable cells compared to the number of control cells. The percent control cells is calculated by multiplying (s.f.) x 100.
  • VP16 and CDDP Materials used in the cytotoxicity assay
  • OM (recombinant E. coli, with s.a. 5 x 10 5 units/mg) was purchased from Genzyme (Cambridge, MA, USA) . After reconstitution in sterile distilled water to a 1 ⁇ g/ml solution, the cytokine was stored at -40°C.
  • OM was added to the cell cultures alone at a concentration of 0.5 ng/ml and 10 ng/ml, or in combination with VP-16 (at concentrations of 0.1 mg/ml, 1 mg/ml, and 2 mg/ml), or with CDDP (at the same concentrations as VP-16) , or with Sant 7 (at concentrations of 5 and 50 ng/ml) , or with the antisense oligonucleotide against the sequence coding for gpl30.
  • VP-16 at concentrations of 0.1 mg/ml, 1 mg/ml, and 2 mg/ml
  • CDDP at the same concentrations as VP-16
  • Sant 7 at concentrations of 5 and 50 ng/ml
  • the oligonucleotides SEQ ID NO : 2 and SEQ ID NO : 3 were designed according to the sequence of cDNA coding for human gpl30 as reported by Hibi et al .
  • the oligonucleotides were synthesized and purified by gel filtration by Cruachem Ltd. (Glasgow, UK) . After reconstitution in RPMI 1640 at a concentration of 1 mM, they were stored at 4°C.
  • oligonucleotides were added directly to the culture medium at 0 h (10 mM) , at 24 hours and 48 hours (5 mM) alone or after 6 hours in combination with OM (100 ng/ml) or VP16 (0.1 mg/ml and 0.5 mg/ml) .
  • Sant 7 instead, was produced as previously reported
  • Mouse monoclonal neutralising antibody anti-human IL-6 (clone: B-E8) was purchased from Biosource International (Camarillo, CA, USA) as a PBS solution. Aliquots (lOmg/ml) were prepared and stored at -40°C, and added to the cell cultures alone or in combination with IL-6 (5 ng/ml, 50 ng/ml and 500 ng/ml) after dilution in complete medium up to the concentration of 1 mg/ml and 0.1 mg/ml .
  • Genistein (GNS, purchased from Sigma Chemical Co. - St. Louis, MO, USA) was reconstituted in a DMSO solution to a concentration of 5 mM and frozen at -20°C. GNS was also added alone at time 0 h or in combination with VP16 (0.1 mg/ml and 1 mg/ml) . Evaluation of effectiveness of combined treatments
  • EXAMPLE 1 Effect of OM on PC-3 cells OM marked with the isotope I, made it possible to ascertain that cultivated PC-3 cells bind OM with a binding specificity equivalent to 7.7 fmoles/10 s cells.
  • the inventors observed that there was no secretion of OM by the PC-3 cells, as assessed by performing an ELISA test in the supernatant of cultivated cells, and the PC-3 cell lysates also did not appear to contain OM.
  • the effect of OM on PC-3 cell growth was then examined. A dose dependent stimulation of cell growth was observed, and a plateau was obtained at a concentration of around 1 ng/ml.
  • CDDP Plus OM Plus OM 0.5 ng/ml 10 ng/ml
  • Dala are the mean ⁇ SD from three different experiments performed in duplicate. The numbers in parenthesis show Ihe extent of cell survival expecled from the effects of OM and CDDP used alone.
  • the cells were seeded at a concentration of 1 x 10 5 cells/ ml/ well in 24-well culture plates. The cells were allowed to adhere overnight At time 0, the reagents were added at appropriate concentrations. After 24-h incubation, the cells were harvested by treatment with trypsln-EDTA. Cell viability was determined by the ability of cells to exiude trypan blue dye. Data are the mean ⁇ SD from three different expenments performed In duplicate The numbers In parentheses show the extent of cell survival expected from the effects of OM and VP-16 used alone For more details see Materials and Methods. * P ⁇ 0.05 observed results versus expected results. " P ⁇ 001 observed results versus expected results.
  • Sant7 is a genetically modified IL-6 mutant, which is characterised by a 70 fold increase in binding affinity to IL6-R , but which is not capable of binding gpl30.
  • the failure to form the IL6-R ⁇ and gpl30 complex blocks signal transduction, so that antibodies directed against IL6, but also the superantagonist Sant7, can be expected to block the IL-6 -mediated effects but not to prevent OM from binding its own receptor complex and therefore cannot be expected to prevent transduction of the OM-induced stimulus.
  • concentration of I.L-6 secreted by PC-3 is approximately 0.15 ng/ml in 24 hour cultures .
  • anti-IL-6 antibodies at a concentration of 0.5 nM or 5 nM the growth of PC-3 is inhibited (Fig. 2A and 2B) .
  • the anti-IL-6 antibodies at a concentration of 0.5 nM are not sufficient to completely antagonise the IL-6 present at a concentration of 0.2 nM
  • a typical formulation to be used to prepare a pharmaceutical composition containing VP16 and CDDP, or more powerful derivatives of said molecules should be as follows:
  • the preparation should not necessarily be administered according to the protocols devised for VP16 and CDDP, since the use of Sant 7 decreases drug- resistance. Furthermore the amount of Sant 7 used in example 3 of the present invention should be adjusted in relation to the body weight by comparison with the data for use of VP16 and CDDP, as amounts expressed in grams per kilogram body weight .
  • Lotem, J., and Sachs, L. Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor ⁇ l and cancer chemotherapeutic compounds in myeloid leukemic cells. Blood, 80: 1750-1757, 1992.
  • Interleukin- 6 functions as an m vitro autocrine growth factor m renal cell carcinoma.
  • Interleukm-6 (IL-6) functions as an autocrine growth factor in cervical carcinomas m vitro. Gynecol . Oncol, 50: 15-19, 1993.
  • IL-6 Endogenous mterleukm-6
  • Yamasaki, K. Taga, T., Hirata, Y., Yawata, H., Kawamshi, Y., Seed, B., Taniguchi , T., Hirano, T., and Kishimoto, T.: Cloning and expression of the human mterleukm-6 (BSF-2/lFN ⁇ 2) receptor. Science (Washington, DC), 241: 825-828, 1988.
  • Hibi M., Murakami, M., Saito, M., Hirano, T., Taga, T., and Kishimoto, T.: Molecular cloning and expression of an IL-6 signal transducer, gpl30. Cell, 63: 1149- 1157, 1990.
  • Paonessa G., Graziani, R., De Serio, A., Savino, R., Ciapponi, L., Lahm, A., Salvati, A.L., Toniatti, C,
  • Ciliberto, G. Two distinct and independent sites on IL-6 trigger gpl30 dimer formation and signalling.
  • Yoshida, K. Taga, T., Saito, M., Suematsu, S., Kumanogoh, A., Tanaka, T., Fujiwara, H., Hirata, M.,
  • Yamagami T., Nakahata, T., Hirabayashi, T., Yoneda, Y.,
  • Oncostatin-M is an autocrine growth factor in Kaposi's sarcoma. Am. J. Pathol., 145: 74-79, 1994.
  • Leu Asp Phe lie Ser Ala Leu Arg Lys Glu Thr Cys Asn Lys Ser Asn 35 40 45
  • Glu Thr Cys Leu Val Lys lie lie Thr Gly Leu Leu Glu Phe Glu Val
  • Lys Ala Lys Asn Leu Asp Ala lie Thr Thr Pro Asp Pro Thr Thr Asn 130 135 140

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Abstract

L'invention porte sur des compositions contenant des agents de chimiothérapie fréquemment utilisés pour le traitement du cancer tels que l'étoposide et la cisplatine combinés à un inhibiteur de la signalisation par le gp130 du complexe récepteur de l'interleukine 6. Ces compositions agissent en réduisant la résistance aux médicaments de lignée de cellules tumorale. Dans l'une de ses réalisations spécifiques, l'invention utilise un super antagoniste de l'interleukine 6, la mutéine de l'IL-6 dite Sant 7, répertoriée dans la liste des séquences sous SEQ ID NO 1, et qui possède la capacité de se fixer à la sous-unités IL-6 Rα du récepteur de l'IL-6. Le Sant 7 inhibe la fixation, par blocage stérique, avec la sous unité gp130 du complexe récepteur de l'IL-6. La transduction du signal de cette cytokine intervient en effet dans les multiples généralement développés par les cellules tumorales suite à une chimiothérapie.
PCT/IT1998/000169 1997-06-20 1998-06-19 Compositions pharmaceutiques anti-tumorales reduisant la resistance aux medicaments des cellules tumorales WO1998058674A1 (fr)

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AU79315/98A AU7931598A (en) 1997-06-20 1998-06-19 Anti-tumour pharmaceutical compositions capable of reducing drug resistance in tumour cells

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IT97RM000368A IT1291932B1 (it) 1997-06-20 1997-06-20 Composizioni farmaceutiche antitumorali capaci anche di ridurre la farmacoresistenza in cellule tumorali, in particolare di carcinoma
ITRM97A000368 1997-06-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005105135A1 (fr) * 2004-04-29 2005-11-10 Applied Research Systems Ars Holding N.V Il-6 pour traitement ou prevention d'une neuropathie induite par une chimiotherapie
WO2006094971A1 (fr) * 2005-03-10 2006-09-14 Universita' Degli Studi 'magna Graecia' Di Catanzaro Combinaison d'antagonistes de l'interleukine-6 et de medicaments antiproliferatifs

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WO1996020728A1 (fr) * 1994-12-29 1996-07-11 Chugai Seiyaku Kabushiki Kaisha Potentialisateur d'agent antitumoral comprenant un antagoniste de l'interleukine 6
WO1996034104A1 (fr) * 1995-04-28 1996-10-31 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Antagonistes de l'interleukine-6 humaine totalement incapables de se lier a la gp130 et leur utilisation pour l'elaboration de composes pharmaceutiques
EP0747480A1 (fr) * 1995-06-07 1996-12-11 Gen-Probe Incorporated Oligonucléotides spécifiques de l'ARNm du transducteur de signal pour les cytokines gp130

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Publication number Priority date Publication date Assignee Title
WO1996020728A1 (fr) * 1994-12-29 1996-07-11 Chugai Seiyaku Kabushiki Kaisha Potentialisateur d'agent antitumoral comprenant un antagoniste de l'interleukine 6
EP0800829A1 (fr) * 1994-12-29 1997-10-15 Chugai Seiyaku Kabushiki Kaisha Potentialisateur d'agent antitumoral comprenant un antagoniste de l'interleukine 6
WO1996034104A1 (fr) * 1995-04-28 1996-10-31 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Antagonistes de l'interleukine-6 humaine totalement incapables de se lier a la gp130 et leur utilisation pour l'elaboration de composes pharmaceutiques
EP0747480A1 (fr) * 1995-06-07 1996-12-11 Gen-Probe Incorporated Oligonucléotides spécifiques de l'ARNm du transducteur de signal pour les cytokines gp130

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Title
Dialog Information Services, File 377, Derwent Drug File, Dialog accession no. 00699459, Derwent accession no. 96-29791, Borsellino N. et al: "Therapeutic agents II (genes, gene components, antireceptors). Effects of an IL-6 receptor super-antagonist (IL-6R SAnt 7) on the growth and sensitivity to etoposide (VP-16) of the hormone resistant and IL-6- secreting prostate tumor PC-3 cell line", Proc.Am.Assoc.Cancer Res.37,87 Meet.,410-411 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005105135A1 (fr) * 2004-04-29 2005-11-10 Applied Research Systems Ars Holding N.V Il-6 pour traitement ou prevention d'une neuropathie induite par une chimiotherapie
EP3124040A1 (fr) * 2004-04-29 2017-02-01 Merck Serono SA Il-6 pour traitement ou prevention d'une neuropathie induite par une chimiotherapie
WO2006094971A1 (fr) * 2005-03-10 2006-09-14 Universita' Degli Studi 'magna Graecia' Di Catanzaro Combinaison d'antagonistes de l'interleukine-6 et de medicaments antiproliferatifs

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IT1291932B1 (it) 1999-01-21
AU7931598A (en) 1999-01-04
ITRM970368A0 (fr) 1997-06-20

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